Sleep deprivation and antidepressant treatment.

4 Pages·2003·0.35 MB·English

by  Voderholzer, Ulrich

Posters & images in neuroscience
Sleep deprivation and antidepressant treatment
The mood-improving effect of sleep deprivation (SD) in depression is even today still not fully
understood.Despite the fact that mood and cognitive functions are lowered by prolonged sleep
loss and despite convincing data that insomnia is a strong risk factor for subsequent depression,1
acute SD for one night or even partial SD in the second half of the night improves mood in
about 60% of depressed patients the day after.2,3 In this respect,among all types of antidepressant
treatments,SD elicits the fastest results,faster even than electroconvulsive therapy.Many authors
correlate the likelihood of responding to SD with clinical variables.A summary of predictors is
listed in Table I.
The main limitation is the transient nature of the effect, and by the frequent relapses after the next night of sleep,
since the majority—but not all—of the improved patients but also by the lack of funding for nonpharmacological
experience a relapse after the next night of sleep.2 and nonneurochemical research. Nevertheless, some
Despite the rapid effects and low risk of relevant side progress has been made within the last few years.A vari-
effects(Table I),2-9the method has remained an “orphan ety of studies have focused on the problem of how to
drug”or “orphan method.”This may be explained not avoid relapses occurring after the next night of sleep and
only by the effort and motivation needed by the patient additionally treated the patients with light therapy,
lithium,or other drugs.Lower relapse rates after SD
were found when SD was combined with one of these
Predictive
therapeutic options (Table II).10-20
•High level of arousal4
A further strategy has been to advance the sleep period
•High variability of mood swings5
to an “unphysiological”time.Several uncontrolled stud-
•Diurnal and day-to-day mood variations6
ies in small numbers of patients have indicated that this
•“Endogenous” and melancholic subtype2,3
phase advance procedure per se acts as an antidepres-
•Bipolar subtype7
sant.More recent studies have combined SD with a sub-
sequent phase advance of the sleep period, over the
Not predictive2,3
course of either six or three nights and consistently found
•Age
that a phase advance of the sleep period stabilizes the
•Sex
antidepressant effect of SD in about 60% of those
•Severity of depression
patients who responded positively to SD.17-20Only one
•Duration of depressive episode
study also included a control group which participated in
•Duration of illness
a phase-delay protocol after SD instead of a phase-
•Earlier treatments
advance protocol.18Significantly more patients relapsed
•Expectation of patients
in the phase-delay protocol compared with the phase
advance protocol (Figure 1).This indicates that the high
Side effects of SD in depression*
•Tiredness, fatigue
•Switch to hypomania or mania in bipolar patients8 •Antidepressants (clomipramine)10
•Exacerbation of psychotic symptoms in psychotically •Lithium11-13
depressed patients9 •Pindolol14
•Lowering of seizure threshold •Light therapy15,16
•Sleep phase advance over 3 to 6 nights17-20
Table I. Clinical predictors of an antidepressant response to sleep depri-
vation (SD) in depressed subjects and side effects. *Not based on Table II. Therapeutic strategies to avoid relapses after successful sleep
systematic documentation. deprivation in depression (selected papers).
Copyright © 2003 LLS SAS. All rights reserved 366
Poster by: Ulrich Voderholzer, MD, PhD
Department of Psychiatry and Psychotherapy,
Klinikum of the Albert-Ludwig-University,
Hauptstrasse 5, 79104 Freiburg, Germany
([email protected])
response rate after SD and phase advance cannot be
12
explained by a placebo phenomenon alone and supports
the hypothesis that,in depressed subjects,sleeping at cer- Delay (n=20)
10
Advance (n=20)
tain phases of the circadian rhythm,ie,especially late in
the night and in the morning,has depressogenic effects. ale 8
Unfortunately,one major issue has been almost com- m sc
plalsettienlgy nefefgelcetcst eadft ebry 4re tsoe a6r cwheeersk:sd,owehsi cShD i sp rtohdeu tcyep aicnayl 6-ite 6
S
period for measuring the effects of antidepressants? DR 4
H
There is only one controlled study using such a design.21
Twenty-four patients received amitriptyline without addi- 2
tional SD,whereas 27 patients received amitriptyline plus
a series of 6 partial SDs.Observer ratings,but not patient 0
0 1 2 3 4 5 6 7 8
ratings,demonstrated superiority of the combined treat-
ment after 4 weeks.By the standards of evidence-based
medicine,there is little evidence to date that SD therapy TSD Advance / delay
has lasting effects over the course of several weeks.
Figure 1. Antidepressant effects of total sleep deprivation (TSD) in one
night with a consecutive phase advance of the sleep period
Neurobiology of SD in depression
(blue circles) in comparison with a phase delay of the sleep
period (gray circles). In the phase-advance group, the antide-
There is no generally accepted hypothesis concerning pressant effect of SD (between day 0 and day 1) was stabilized
until day 8, whereas in the phase-delay group mood worsened
the mechanism of action of SD,nor an explanation for
again (mood was measured by a short version of the Hamilton
the observation that subsequent sleep after SD leads to Depression Rating Scale [HDRS], containing 6 items). This scale
relapses. A variety of neurobiological effects point is suitable for frequent ratings, whereas the 21-item HDRS
toward potential mechanisms of action of the procedure would not have been adequate within the study design.18
(Table III).22-32
Based on the observations that hyperarousal and a high •Decrease in limbic hypermetabolism22-24
level of activation predict a favorable SD response,4the •Increase in dopamine turnover25
antidepressant effect was explained using the two-process •Increase in peripheral cytokines26,27
model of sleep regulation (Figure 2).33 In this model, •Increase in cortisol28-30
depressed patients have a deficiency of process S (ie,sleep •Increase in growth hormone secretion (recovery sleep)30
need) with process C (circadian rhythm) remaining unaf- •Increase in thyroid hormones31,32
fected.Depression is characterized by a deficient build-up
Table III. Neurobiological effects of sleep deprivation.In humans some
of process S (Figure 2).SD transiently leads to an increase of the studies were performed in depressed patients, while
in process S to normal, whereas relapse occurs after other studies were in healthy subjects or in depressed patients
and healthy subjects.
“recovery sleep”due to a return to low levels of S.
Several brain imaging studies have tried to correlate the significant decreases in metabolic rates occurred in the
SD response with metabolic states of certain brain areas. medial prefrontal cortex and frontal pole in the patients
Two early studies using single photon emission computed who responded positively to SD.The brain imaging stud-
tomography (SPECT)22and positron emission tomogra- ies convincingly demonstrated that acute antidepressant
phy (PET),23respectively,found higher metabolic rates SD is able to change metabolic states of brain areas that
in limbic areas in responders compared with nonrespon- are involved in mood regulation.
ders.A more recent study24confirmed these earlier find- Many studies have assessed endocrine parameters before
ings: responders to SD had higher relative metabolic and after SD.The results have been inconsistent,which
rates in the ventral anterior cingulate and in the medial may be partially explained by methodological shortcom-
prefrontal cortex (Figure 3),as well as in the posterior ings.Several authors favor the hypothesis that the hypo-
subcallosal gyrus at baseline than depressed patients who thalamo-pituitary-thyroid (HPT) axis plays a key role in
did not respond to SD and normal volunteers.After SD, mediating the antidepressant effects of SD.31,32
367 www.dialogues-cns.org
Posters & images in neuroscience
Another issue is the impact of SD on the hypothalamo-
S pituitary-adrenal (HPA) axis.Increased activity of this
ess axis is one of the most consistent abnormalities in depres-
c
o
pr S sion and normalization of this hyperactivity is a correlate
of of clinical remission and has been suggested as the mech-
el
v anism of action of antidepressant treatment.34In healthy
e
L C
humans,acute SD increases cortisol secretion.28,29 In a
study that we conducted ourselves,we found a significant
6 16 23 46 16 23 4 6 stimulatory effect of acute SD on nighttime cortisol in a
Clock time group of unmedicated depressed subjects,which was not
related to treatment response.30However,during the first
Sleep deprivation e
v
ocess S depressioms Figure 2. TTawshsious -mpmrinoocgde etslhs c amat noa dnee xilnp oslauf ifsnflie cteihepen d ta ebnputriiidlvdae-tpuiorpen so s(fSa Dpnr)to aecnfefdse sdc Ste po(Srfe ssStsDaion nbd ys.
evel of pr crease in sympt ftdoheruc ssrel,e aelespea sdn iepnergod c)t,e oSs sDt hS te rta oan nbsitaeisndetellipyn rieen sclesreavanesltse esle ftfahedeci ntl.eg vR eteol co rofe vlpearproysc ees lsiense tSpo,
L De the depressed state. This model fits well with clinical observa-
tions that depressed patients have hyperarousal, which has
been shown to be a positive predictor of the SD response.4
6 16 23 46 16 23 4 6 Reproduced from reference 33: Borbély AA, Wirz-Justice A. Sleep, sleep
Clock time deprivation and depression. Hum Neurobiol. 1982;1:205-210. Copyright
© 1982, Springer Verlag.
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368
Poster by: Ulrich Voderholzer
half of the day after the night,SD responders in contrast Z :
to nonresponders had higher cortisol concentrations -4.00 mm
Percent
compared with the day before SD.This finding does not Y
difference
necessarily contradict the above relationship between 6.0
+20.00
depression and HPA axis hyperactivity for two reasons.
First,the acute effects of antidepressant treatments on +13.33 3.0
the HPA axis may differ from the chronic effects.It has +6.67
been shown that electroconvulsive treatment and anti- 0.0
±0.00
depressants also initially stimulate the HPA axis.Second,
two studies demonstrated acute antidepressant effects of -6.67 -3.0
cortisol infusion compared with placebo.35,36 -13.33
Another theory that possibly provides a link to the HPA -6.0
-20.00
effects of SD focuses on the psychostimulant effects. %
Earlier studies reported an increase in dopamine,norepi- X -9.0
nephrine,and serotonin after SD,ie,similar neurobiolog-
-6 -3 0 +3 +6 cm
ical effects as after the intake of psychostimulants like
amphetamines (see reference 25 for an overview).Support
Figure 3. Positron emission tomography (PET) scan of depressed patients
for a psycho-stimulant theory also comes from brain imag-
who respond to total sleep deprivation (SD) in one night.24At
ing data,demonstrating effects of psychostimulants such
baseline, responders to SD had higher metabolic rates in the
as amphetamines on metabolic rates similar to those ventral anterior cingulate and in the medial prefrontal cortex.
observed in SD.37Since there is a functional coupling of The study confirmed earlier findings demonstrating an asso-
ciation between high metabolic rates in limbic areas and the
psychostimulant effects and the HPA axis,38 a cortisol
likelihood to respond to SD.22,23
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mitter release.
J Psychiatry. 1999;156:1149-1158. Copyright © 1999, American
Psychiatry Association.
In summary,the SD response in depressive patients remains a highly interesting issue for
depression research,since,contrary to all antidepressant drugs,it may significantly ameliorate
mood within one day.Understanding this effect and optimizing the duration of the effect,ie,
preventing relapse after the response,might improve our ability to treat depression.
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369